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Unusual ocular presentation of von HippelLindau disease

Alejandra Valenzuela,* MD; Harriet Druker, MSc; David Malkin, MD, FRCPC; Brenda Gallie,* MD, FRCPS; Elise Hon,* MD, FRCPS
ABSTRACT RSUM Case report: We report a young girl who first presented with a unilateral total exudative retinal detachment diagnosed as Coats disease. Eight years later, when she presented with classical retinal hemangioblastomas with reduced vision in the fellow eye, the diagnosis of von Hippel-Lindau (VHL) disease was confirmed. Comments: This case highlights the importance of considering the possibility of VHL in atypical cases of Coats disease and unusual sporadic cases of unexplained unilateral exudative retinal detachment. The identification of VHL mutations and subsequent screening allows early diagnosis and treatment of asymptomatic retinal or central nervous system hemangioblastomas, as well as other malignancies associated with this syndrome. Observation : Nous faisons tat dune jeune fille qui stait dabord prsente avec un dcollement de rtine exsudatif total et unilatral, diagnostiqu comme tant la maladie de Coats. Huit annes aprs, quand elle sest prsente avec des hmangioblastomes rtiniens classiques avec baisse de vision de lautre il, on a confirm le diagnostic du syndrome von Hippel-Lindau (VHL). Commentaires : Ce cas souligne limportance de considrer la possibilit du VHL pour les cas atypiques de la maladie de Coats et les cas sporadiques et inusits de dcollement de rtine exsudatif unilatral inexpliqu. Lidentification des mutations et les dpistages subsquentes permettent de diagnostiquer et de traiter rapidement les hmangioblastomes asymptomatiques de la rtine et du systme nerveux central, de mme que les autres malignits associes ce syndrome.

From *the Department of Ophthalmology and Visual Sciences, The Hospital for Sick Children, Toronto, Ont., the Department of Pediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ont., and Cancer Informatics, Princess Margaret Hospital, University Health Network, Toronto, Ont. Originally received May 17, 2004 Accepted for publication Nov. 17, 2004 Correspondence to: Dr. Elise Hon, Department of Ophthalmology and Visual Sciences, The Hospital for Sick Children, 555 University Ave., Elm Wing, Rm. M165, Toronto ON M5G 1X8; fax (416) 813-8266; eheon@attglobal.net This article has been peer-reviewed. Can J Ophthalmol 2005;40:5937

on Hippel-Lindau (VHL) disease is a hereditary phakomatosis that principally produces vascular, neoplastic, and cystic lesions in mesoderm-derived structures.1 The syndrome is characterized by a variety of manifestations, including hemangioblastomas in the retina, cerebellum, other parts of the brain, and spinal cord; angiomas of the liver and kidney; adenomas of the epididymis and kidney; renal cell carcinoma; pheochromocytoma; and cysts of the pancreas, kidney, and epididymis.15 The condition usually presents with neurological symptoms or visual disturbance or both; early treatment offers a better prognosis.1,4,5 Treatment of

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B B

Fig. 1Right eye, age 7.A: Complete exudative retinal detachment with cholesterol crystals underlying retina. B: Normal left posterior pole.

retinal hemangioblastomas depends on the size, amount of leakage, and location of the tumors, but it can prevent progression to an extensive exudative retinal detachment and marked visual loss.510 We report a young girl who first presented with a unilateral total exudative retinal detachment diagnosed as Coats disease. Eight years later, when she presented with classical retinal hemangioblastomas with reduced vision in the fellow eye, the diagnosis of VHL disease was confirmed.
CASE
REPORT

Fig. 2Right eye, age 15. A: Two hemangiomas along inferotemporal vascular arcade, plus secondary exudative retinal detachment. B: Superotemporal hemangioblastoma with retinal detachment outlined with subretinal exudates.

A 7-year-old girl, with no vision in her right eye since age 2 years, presented with a right leukocoria. On examination, she had no light perception in the right eye and 20/20 vision in her left. A right afferent

pupillary defect and a right sensory exotropia were noted. Intraocular pressures were 16 mm Hg in the right eye and 12 mm Hg in the left. Fundus examination of the right eye showed a complete exudative retinal detachment with cholesterol crystals underlying the retina, but no abnormal telangiectatic vessels could be specifically identified (Fig. 1A). The left eye was entirely normal (Fig. 1B). Computed tomography (CT) scans of the head and orbit showed no ocular, orbit, or central nervous system tumours. The child was otherwise healthy and did not have any past medical problems or pertinent familial history. The diagnosis of a right Coats disease was proposed and

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Fig. 3Right eye, age 15. B-scan ultrasound identifying peripheral hemangioblastoma.

the family opted for a conservative management with monitoring of the right intraocular pressure. At age 15, she presented with a 4-day history of floaters and reduced visual acuity. She had no light perception in the right eye and 20/70 vision in the left eye. Intraocular pressures were 32 mm Hg (right) and 10 mm Hg (left). The right eye was found to have a shallow anterior chamber, moderate iris neovascularization with some areas of angle closure, a partially reabsorbed cataract, and the unchanged total exudative retinal detachment. B-scan ultrasound showed a right shallow anterior chamber with a total funnel retinal detachment in contact with the posterior surface of the lens. The axial length was significantly reduced and there was some scleral calcification reflecting a right phthisis bulbi. The left anterior segment was completely normal. However, 3 large hemangiomas were evident on examination of the left retina. Two hemangiomas along the infratemporal vascular arcade were well connected by a dense preretinal membrane, and the third was in the superotemporal periphery (Fig. 2A and 2B). A secondary exudative inferior retinal detachment from 2 to 7 oclock positions partially involved the macula. B-scan ultrasound imaging of the left eye identified a homogeneous well-defined soft-tissue density elevation at the posterolateral aspect of the globe, consistent with a retinal hemangioblastoma (Fig. 3). CT scans of the head, orbit, and abdomen were normal.

Family history revealed that a paternal aunt had kidney surgery at age 12 for unknown reason, whose daughter was reported to have poor vision in her left eye due to retinal problems. These individuals were not available. Genetic testing for VHL found her to be heterozygous for deletion of a single base (delG, guanine) at nucleotide 594 of the VHL gene, resulting in a shift in the translational frame of the mRNA after amino acid 128 and causing a premature stop codon at position 158. In the next 11 months, the patient went through 5 different complex vitreoretinal surgeries in her left eye, including multiple preretinal membrane peelings, endolaser photocoagulations, cryopexies, and a scleral buckle procedure. She developed 3 consecutive total bullous retinal detachments with additional complications of macular dragging, chronic cystoid macular edema with a macular hole, subretinal fibrosis, and anterior and posterior vitreoretinal proliferation that required leaving silicone oil in the eye to maintain the retina in an anatomic position. Unfortunately, last-recorded best-corrected vision was hand movements at 30 cm.
COMMENTS

Von Hippel-Lindau disease occurs in 1 of 36 000 births per year,11 is panethnic, and inherited in an

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autosomal dominant manner. The diagnosis of VHL syndrome is suspected in individuals with characteristic lesions including hemangioblastomas, renal cysts and renal cell carcinoma, pheochromocytoma, and endolymphatic sac tumors. Molecular genetic testing of the tumor suppressor gene VHL (chromosomal locus 3p26-p25) detects mutations in nearly 100% of patients who meet the clinical diagnostic criteria for the condition.12 Four phenotypes of VHL syndrome are distinguished by the presence of pheochromocytoma or renal cell carcinoma.13 Retinal angiomas and central nervous system hemangioblastomas occur in all 4 types. Type 2 VHL is characterized by a high risk of concurrent pheochromocytoma, whereas type 1 VHL is not. Type 2 VHL families can be further subdivided into type 2A (low risk of renal cell carcinoma), type 2B (high risk of renal cell carcinoma), and type 2C (exclusively pheochromocytoma without other characteristics of VHL disease). In general, missense mutations are associated with development of type 2 VHL, whereas mutations that lead to truncated VHL protein and gross gene deletions are primarily associated with type 1 disease.14 Our patient was found to carry a heterozygous single-base deletion that encodes a frameshift mutation and predicted truncated protein, placing her in the type 1 VHL category and at low risk to develop pheochromocytoma. More than 50% of the affected patients present with retinal hemangioblastomas, which are bilateral and multiple in more than half the cases.4,5 If left untreated, or if treatment is delayed, the vision may be lost because of cystoid macular edema, subretinal exudates, exudative or tractional retinal detachment, vitreous hemorrhage, or macular traction due to epiretinal membranes, as presented in this report.8,10 Some patients may require enucleation for a painful neovascular glaucoma, or they may ultimately develop phthisis bulbi.4,5 Undetected systemic manifestations can produce severe complications or even death. Screening of affected patients and family members who are at risk should continue throughout their lifetimes because manifestations of this syndrome may occur at any age.5 Current recommendations include annual physical examination for neurological signs and abdominal masses, renal ultrasound, ophthalmic examination, and 24-hour urinary vanillylmandelic acid (VMA) tests. Magnetic resonance imaging of the head and spine is generally performed

every 3 years, or sooner if signs or symptoms are present. The potential for multiorgan involvement indicates that management of these patients and their families should take place in a multidisciplinary setting.5 This case highlights the importance of considering the possibility of VHL in atypical cases of Coats disease and unusual sporadic cases of unexplained unilateral exudative retinal detachment.1517 The identification of VHL mutations and subsequent screening allows early diagnosis and treatment of asymptomatic retinal or central nervous system hemangioblastomas, as well as other malignancies related to this syndrome.
REFERENCES
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19932005. Available: http://www.genetests.org (accessed 2004 Apr 14). 13. Chen F, Kishida T, Yao M, et al. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat 1996;8:34857. 14. Ohh M, Kaelin WG Jr. The von Hippel-Lindau tumour suppressor protein: new perspectives. Molec Medicine Today 1999; 5:25763. 15. Ferguson A, Singh J. Total exudative detachment as a first presentation of von Hippel-Lindau disease. B J Ophthalmol 2002;86:7012.

16. Schindler RF, Sarin LK, MacDonald PR. Hemangiomas of the optic disc. Can J Ophthalmol 1975;10:30518. 17. Nicholson DH, Anderson LS, Blodi C. Rhegmatogenous retinal detachment in angiomatosis retinae. Am J Ophthalmol 1986;101:1879. Key words: total retinal detachment, Coats disease, von HippelLindau, hemangioblastomas

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